{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T08:12:38Z","timestamp":1789719158746,"version":"4.0.1"},"reference-count":60,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T00:00:00Z","timestamp":1750032000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AI119446"],"award-info":[{"award-number":["R01 AI119446"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:p>\n                    Polymyxins are used against highly resistant Gram\u2010negative pathogens, and nephrotoxicity (acute kidney injury, AKI) is the major dose\u2010limiting adverse effect. We aimed to develop a well\u2010informed population pharmacokinetic\/toxicodynamic (PK\/TD) model using the largest polymyxin B\u2010treated critically ill patient population studied to inform polymyxin B dosing strategies. Critically ill patients receiving intravenous polymyxin B for at least 48\u2009hours were enrolled in an observational study. Serum creatinine (SCr) concentrations were collected from electronic medical records. PK\/TD analysis and Monte Carlo simulations were performed to determine the probability of AKI,\n                    <jats:italic>P<\/jats:italic>\n                    (AKI), for clinically relevant treatments. Patients (\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u2009117) aged 18\u201394 received intravenous polymyxin B (1.33\u20136.00\u2009mg\/kg\/day) for 1\u201350\u2009days. The changes in SCr were described using an indirect response model. The effects of polymyxin B\u2010induced functional kidney injury were characterized using 9 transit compartments (mean time to onset ~7\u2009days), leading to a reduction in SCr elimination. Sex was identified as a significant covariate for baseline SCr\n                    <jats:sub>0<\/jats:sub>\n                    . Concomitant amikacin or vancomycin use resulted in increased sensitivity to polymyxin B. On day 21, Low (\n                    <jats:italic>f<\/jats:italic>\n                    AUC\n                    <jats:sub>0\u201324<\/jats:sub>\n                    ,\n                    <jats:sub>SS<\/jats:sub>\n                    \u2009=\u2009~10\u2009mg\u00b7h\/L), medium (\n                    <jats:italic>f<\/jats:italic>\n                    AUC\n                    <jats:sub>0\u201324,SS<\/jats:sub>\n                    \u2009=\u2009~20\u2009mg\u00b7h\/L\u2009), and high (\n                    <jats:italic>f<\/jats:italic>\n                    AUC\n                    <jats:sub>0\u201324,SS<\/jats:sub>\n                    \u2009=\u2009~40\u2009mg\u00b7h\/L) drug exposures resulted in a\n                    <jats:italic>P<\/jats:italic>\n                    (AKI) (&gt;\u20091\u2010fold SCr increase) of 25.8%, 32.5%, and 40.4%, respectively. This study, the largest to date, suggests that regimens ranging from low to high polymyxin B exposures can minimize\n                    <jats:italic>P<\/jats:italic>\n                    (AKI) over a longer duration (14\u2009days). However, supratherapeutic exposure can be administered relatively safely when limited to a shorter duration (\u2264\u20094\u2009days). The population PK\/TD model may be used to improve polymyxin B dosing to help conserve this last\u2010line agent.\n                  <\/jats:p>","DOI":"10.1002\/cpt.3729","type":"journal-article","created":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T00:54:52Z","timestamp":1750121692000},"page":"841-852","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Population Pharmacokinetic\/Toxicodynamic Model for Polymyxin B in Critically Ill Patients to Identify the Risk of Nephrotoxicity"],"prefix":"10.1002","volume":"118","author":[{"given":"Patrick O.","family":"Hanafin","sequence":"first","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3951-1146","authenticated-orcid":false,"given":"Ramya","family":"Mahadevan","sequence":"additional","affiliation":[{"name":"Titus Family Department of Clinical Pharmacy, USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences University of Southern California  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8704-7770","authenticated-orcid":false,"given":"Gauri G.","family":"Rao","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"},{"name":"Titus Family Department of Clinical Pharmacy, USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences University of Southern California  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5331-4837","authenticated-orcid":false,"given":"Alexandre P.","family":"Zavascki","sequence":"additional","affiliation":[{"name":"Infectious Diseases Service, Hospital Moinhos de Vento  Porto Alegre Brazil"},{"name":"Department of Internal Medicine, Medical School Universidade Federal, do Rio Grande do Sul  Porto Alegre Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Maria","family":"Sandri","sequence":"additional","affiliation":[{"name":"Infectious Disease Service, Hospital S\u00e3o Lucas da Pontif\u00edcia Universidade Cat\u00f3lica do Rio Grande do Sul  Porto Alegre Brazil"},{"name":"Department of Internal Medicine, Medical School Universidade Federal de Ci\u00eancias da Sa\u00fade de Porto Alegre\/Rio Grande do Sul  Porto Alegre Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Kwa","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Singapore General Hospital  Singapore City Singapore"},{"name":"Emerging Infectious Diseases, Duke\u2010NUS Medical School  Singapore City Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1091-6130","authenticated-orcid":false,"given":"Marc H.","family":"Scheetz","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice Midwestern University Chicago College of Pharmacy  Downers Grove Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine J.","family":"Kubin","sequence":"additional","affiliation":[{"name":"New York\u2010Presbyterian Hospital, Columbia University Irving Medical Center  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayesh","family":"Shah","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Internal Medicine Columbia University Vagelos College of Physicians and Surgeons  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin P.Z.","family":"Cherng","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases Singapore General Hospital  Singapore City Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael T.","family":"Yin","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Internal Medicine Columbia University Vagelos College of Physicians and Surgeons  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiping","family":"Wang","sequence":"additional","affiliation":[{"name":"Biomedicine Discovery Institute Monash 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